{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:49:23Z","timestamp":1789544963846,"version":"build-2803163510"},"reference-count":44,"publisher":"Rockefeller University Press","issue":"13","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,12,14]]},"abstract":"<jats:p>Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell\u2013like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small molecule IRAK4 inhibitors, ND-2158 and ND-2110. These small molecules suppressed LPS-induced TNF production, alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLBCL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-\u03baB and autocrine IL-6\/IL-10 engagement of the JAK\u2013STAT3 pathway. In ABC DLBCL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton\u2019s tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacological inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLBCL, and possibly other malignancies dependent on aberrant MYD88 signaling.<\/jats:p>","DOI":"10.1084\/jem.20151074","type":"journal-article","created":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T03:38:22Z","timestamp":1448941102000},"page":"2189-2201","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":144,"title":["Selective interleukin-1 receptor\u2013associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy"],"prefix":"10.1084","volume":"212","author":[{"given":"Priscilla N.","family":"Kelly","sequence":"first","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna L.","family":"Romero","sequence":"additional","affiliation":[{"name":"Nimbus Therapeutics, Cambridge, MA 02141 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Yang","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Arthur L.","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Nimbus Therapeutics, Cambridge, MA 02141 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaughnessy","family":"Robinson","sequence":"additional","affiliation":[{"name":"Schr\u00f6dinger, New York, NY 10036 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Miao","sequence":"additional","affiliation":[{"name":"Nimbus Therapeutics, Cambridge, MA 02141 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Rui","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William F.","family":"Westlin","sequence":"additional","affiliation":[{"name":"Nimbus Therapeutics, Cambridge, MA 02141 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosana","family":"Kapeller","sequence":"additional","affiliation":[{"name":"Nimbus Therapeutics, Cambridge, MA 02141 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis M.","family":"Staudt","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2015,11,30]]},"reference":[{"key":"2023072602394339100_bib1","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/35000501","article-title":"Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling","volume":"403","author":"Alizadeh","year":"2000","journal-title":"Nature."},{"key":"2023072602394339100_bib2","first-page":"377","article-title":"Animal models of rheumatoid arthritis","volume":"1","author":"Bendele","year":"2001","journal-title":"J. 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